Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2014-04

AUTHORS

Julia Kozlitina, Eriks Smagris, Stefan Stender, Børge G Nordestgaard, Heather H Zhou, Anne Tybjærg-Hansen, Thomas F Vogt, Helen H Hobbs, Jonathan C Cohen

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease. To elucidate the molecular basis of NAFLD, we performed an exome-wide association study of liver fat content. Three variants were associated with higher liver fat levels at the exome-wide significance level of 3.6 × 10(-7): two in PNPLA3, an established locus for NAFLD, and one (encoding p.Glu167Lys) in TM6SF2, a gene of unknown function. The TM6SF2 variant encoding p.Glu167Lys was also associated with higher circulating levels of alanine transaminase, a marker of liver injury, and with lower levels of low-density lipoprotein-cholesterol (LDL-C), triglycerides and alkaline phosphatase in 3 independent populations (n > 80,000). When recombinant protein was expressed in cultured hepatocytes, 50% less Glu167Lys TM6SF2 protein was produced relative to wild-type TM6SF2. Adeno-associated virus-mediated short hairpin RNA knockdown of Tm6sf2 in mice increased liver triglyceride content by threefold and decreased very-low-density lipoprotein (VLDL) secretion by 50%. Taken together, these data indicate that TM6SF2 activity is required for normal VLDL secretion and that impaired TM6SF2 function causally contributes to NAFLD. More... »

PAGES

352-356

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/ng.2901

DOI

http://dx.doi.org/10.1038/ng.2901

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1008453458

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/24531328


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curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/pub.10.1038/ng.2901'

Turtle is a human-readable linked data format.

curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1038/ng.2901'

RDF/XML is a standard XML format for linked data.

curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1038/ng.2901'


 

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